Tryptophan Metabolism in Mosquitoes

描述(申请人提供)：蚊子传播的疾病，如疟疾；继续对人类健康造成破坏性影响。近年来，西尼罗河病毒已经在世界各地的几个地区出现，它在美国的快速传播表明它可能会在美国永久存在。为了防止蚊媒疾病的传播，迫切需要开发新的蚊子控制方法，而彻底了解蚊子媒介的生物化学和生理对于开发新的创新媒介控制策略是必不可少的。我们对埃及伊蚊体内色氨酸代谢的研究揭示了蚊子体内色氨酸分解代谢的一些独特方面。犬尿氨酸、3-羟基犬尿氨酸(3-HK)、犬尿酸(KA)和黄尿酸(XA)是色氨酸分解代谢的关键组分，犬尿氨酸到KA和3-HK到XA的途径由犬尿氨酸转氨酶(KAT)和/或3-羟基犬尿氨酸转氨酶(HKT)介导，在蚊子发育过程中发挥着重要的生理作用。我们的数据表明KA对于维持蚊子中枢神经系统的正常生理功能是必不可少的，3-HK到XA的途径是蚊子解毒3-HK的机制，KAT和HKT的分子调控为平衡蚊子体内色氨酸分解代谢的各个分支途径提供了一种机制。蚊虫Kat和HKT都与哺乳动物有很高的序列同源性，但它们的底物特异性和动力学性质似乎与类似的哺乳动物酶有很大不同。根据我们的结果，我们假设蚊子凯特和香港蚊子都经历了实质性的功能进化，以满足它们在发育过程中对蚊子的特定代谢需求。这项建议的目的是(1)清楚界定KAT和HKT在蚊子中所扮演的角色，(2)了解这些蚊子转氨酶与其他物种对应的酶的功能演变，以及(3)阐明埃及伊蚊和HKT的催化功能的结构基础。拟议的研究将有助于我们全面了解蚊子体内的色氨酸代谢。由于KAT和HKT在蚊子发育过程中都是至关重要的，它们可能是未来控制蚊子的潜在目标。

DESCRIPTION (provided by the applicant): Mosquito transmitted diseases, such as malaria; continue to have a devastating impact on human health. In recent years, the West Nile virus has emerged in several regions around the world and its rapid spread in the United States suggests its potential permanent establishment in the country. To prevent the transmission of mosquito-borne diseases, there is an urgent need for new mosquito control methods to be developed and a thorough understanding of the biochemistry and physiology of the mosquito vectors is imperative to the development of new and innovative vector control strategies. Our studies dealing with tryptophan metabolism in Aedes aegypti revealed some unique aspects of tryptophan catabolism in mosquitoes. Kynurenine, 3-hydroxykynurenine (3-HK), kynurenic acid (KA) and xanthurenic acid (XA) are the key components in the tryptophan catabolism, and kynurenine to KA and 3-HK to XA pathways, mediated by kynurenine aminotransferase (KAT) and/or 3-hydroxykynurenine transaminase (HKT), play important physiological roles in mosquitoes during development. Our data suggest that KA is essential for maintaining the normal physiological function of mosquito central nervous system, that the 3-HK to XA pathway is the mechanism by which mosquitoes detoxify 3-HK, and that the molecular regulation of KAT and HKT provides a mechanism for balancing the individual branch pathways of tryptophan catabolism in the mosquitoes. Both mosquito KAT and HKT share high sequence identity with their mammalian counterparts, but their substrate specificity and kinetic properties seem quite different from those of similar mammalian enzymes. Based on our results, we hypothesize that both mosquito KAT and HKT have undergone substantial functional evolution to meet their specific metabolic requirements in mosquitoes during development. The objectives of this proposal are (1) to clearly define the roles both KAT and HKT play in mosquitoes, (2) to understand the functional evolution of these mosquito transaminases in comparison with counterpart enzymes from other species, and (3) to elucidate the structural basis of catalytic functions for both A. aegypti KAT and HKT. The proposed studies will contribute to our overall knowledge of tryptophan metabolism in mosquitoes. Because both KAT and HKT are critical during mosquito development, they could be potential targets for future mosquito controls.